EP1805181B1 - Purinderivate zur verwendung als agonisten des adenosin-a-2a-rezeptors - Google Patents

Purinderivate zur verwendung als agonisten des adenosin-a-2a-rezeptors Download PDF

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EP1805181B1
EP1805181B1 EP05797944A EP05797944A EP1805181B1 EP 1805181 B1 EP1805181 B1 EP 1805181B1 EP 05797944 A EP05797944 A EP 05797944A EP 05797944 A EP05797944 A EP 05797944A EP 1805181 B1 EP1805181 B1 EP 1805181B1
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formula
compound
optionally substituted
amino
purin
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EP1805181A1 (de
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Robin Alec Fairhurst
Roger John Taylor
Paul Singh
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Novartis AG
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Novartis AG
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Priority claimed from GB0514619A external-priority patent/GB0514619D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • This invention relates to organic compounds, their preparation and use as pharmaceuticals.
  • the present invention provides compounds of formula I in free or salt form, wherein
  • 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur may be, for example, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, morpholino, triazine, oxazine or thiazole.
  • Preferred heterocyclic rings include piperazine, pyrrolidine, morpholino, imidazole, isotriazole, pyrazole, tetrazole, thiazole, thiadiazole, pyridine, piperidine, pyrazine, furan, oxazole, isoxazole, oxadiazole and azetidine.
  • the 5- or 6-membered heterocyclic ring can be unsubstituted or it can be substituted at one or more positions, preferably one or two positions, by halo, cyano, oxo, hydroxy, carboxy, amino, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkylsulfonyl, aminocarbonyl, C 1 -C 8 -alkylcarbonyl or C 1 -C 8 -alkoxy optionally substituted at one or more positions, preferably one or two positions, by aminocarbonyl.
  • Especially preferred substituents include methyl, ethyl, d propyl) and amino.
  • R 5 is preferably unsubstituted imidazolyl, unsubstituted piperidinyl, or imidazolyl substituted at one position by C 1 -C 3 -alkyl.
  • R 6 is preferably pyrrolidinyl, piperidinyl or piperazinyl and, where relevant, R 7 is preferably unsubstituted thiophenyl, unsubstituted pyridinyl, unsubstituted pyrrolidinyl, pyridinyl disubstituted by chloro, piperazinyl substituted Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
  • R 2 is hydrogen, unsubstituted C 1 -C 6 -alkyl or C 1 -C 5 -alkyl substituted at one position by C 6 -C 10 -aryl;
  • R 3 is halo or C 2 -C 6 -alkynyl, or R 3 is amino optionally substituted at one position by C 3 -C 6 -cycloalkyl optionally substituted at one position by amino, or R 3 is C 1 -C 4 -alkylamino substituted at one or two positions by
  • R 2 is hydrogen or C 1 -C 6 -alkyl optionally substituted by C 6 -C 10 -aryl;
  • R 3 is halo or C 2 -C 5 -alkynyl, or R 3 is amino optionally substituted by C 3 -C 8 -cycloalkyl optionally substituted by amino, or R 3 is C 1 -C 4 -alkylamino optionally substituted by hydroxy, C 6 -C 8 -aryl or by R 5 , or R 3 is R 6 optionally
  • the compounds represented by formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • R 2 is hydrogen or C 1 -C 8 -alkyl optionally substituted by C 6 -C 10 -aryl;
  • R 3 is halo or C 2 -C 8 -alkynyl, or R 3 is amino optionally substituted by C 3 -C 8 -cycloalkyl optionally substituted by amino, or R 3 is C 1 -C 8
  • R 2 is hydrogen or C 1 -C 6 -alkyl optionally substituted by C 6 -C 10 -aryl;
  • R 3 is halo or C 2 -C 5 -alkynyl, or R 3 is amino optionally substituted by C 3 -C 8 -cycloalkyl optionally substituted by amino, or R 3 is C 1 -C 4 -alkylamino optionally substituted by hydroxy, C 6 -C 8 -aryl or by R 5 , or R 3 is R 6 optionally
  • R 2 and R 3 are as hereinbefore defined, with a compound of formula III R 1 -X a III or a formula IIIa wherein R 1 is C 1 -C 8 -alkylcarbonyl, C 3 -C 8 -cycloalkylcarbonyl or C 7 -C 14 -aralkylcarbonyl, X a is a leaving group and K is hydrogen, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy, in the presence of a base;
  • Process variant (A) may be carried out using known procedures for reacting amines with acid halides, acid anhydrides or mixed anhydrides e.g. carboxylic and carbonic anhydrides (or amide-forming derivatives thereof such as carboxylic acids) or sulfonyl halides e.g. mesyl halides, or analogously as hereinafter described in the Examples.
  • the leaving group may be any suitable leaving group, for example halo, -SO 2 -C 1 -C 8 -alkyl or -SO 2 -C 6 -C 10 -aryl.
  • reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran (THF), in the presence of a base, for example diisopropylethylamine (DIPEA).
  • a base for example diisopropylethylamine (DIPEA).
  • Suitable reaction temperatures are from 10° C to 40° C, preferably room temperature.
  • Process variant (B) may be carried out using known procedures for reacting halides, especially aromatic halides, with amines, or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example dichlorobenzene, dimethylsulfoxide, acetonitrile or N-methyl-pyrrolidone (NMP) or mixtures thereof op tionally in the presence of a catalyst, such as sodium iodide, and a base, such as triethylamine.
  • Suitable reaction temperatures are from 100° C to 250° C, preferably between 120° C to 220° C, especially about 170° C, for example by heating with microwave radiation.
  • Process variant (C) may be carried out using known procedures for reacting halides with amines, or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran, preferably in an inert atmosphere, for example argon, optionally in the presence of a base, for example diisopropylethylamine.
  • Suitable reaction temperatures from 0° C to 70° C, preferably between 40° C to 60° C, especially about 50° C.
  • Process variant (D) may be carried out using known procedures for cleaving ester bonds, for example using a strong organic acid, such as trifluoroacetic acid.
  • the reaction is conveniently carried out using an organic solvent, for example dichloromethane (DCM).
  • Suitable reaction temperatures are from 0° C to 40° C, preferably room temperature.
  • Process variant (E) may be carried out using known procedures for reacting amines with acyl-imidazoles or isocyanates, or analogously as hereinafter described in the Examples.
  • T in formula X is preferably imidazolyl.
  • the reaction is conveniently carried out using an organic solvent, for example toluene and/or isopropyl alcohol. Suitable reaction temperatures are from 0° C to 40° C, preferably room temperature.
  • Process variant (F) may be carried out using known procedures for reacting halides with alkynes, or analogously as hereinafter described in the Examples.
  • the catalyst is preferably a palladium catalyst (together with a CuI salt) and the base is preferably butylamine.
  • the reaction is conveniently carried out using an organic solvent, such as dimethylformamide (DMF). Suitable reaction temperatures are from 40° C to 200° C, preferably 80° C to 160° C, especially about 120° C.
  • Process variant (G) may be carried out using known procedures for reacting carboxylic acid alkyl esters with amines, or analogously as hereinafter described in the Examples.
  • the base is preferably is preferably imidazole.
  • the reaction is conveniently carried out using an organic solvent, such 1,2-dichloroethane, iso-propanol or a mixture thereof. Suitable reaction temperatures are from room temperature to 250° C, preferably 50° C to 100° C.
  • Process variant (H) may be carried out using known procedures for sulfonylating heterocycles, or analogously as hereinafter described in the Examples.
  • the sulphonylating agent is preferably an alkylsulfonylhalide, for example mesylchloride.
  • the base is preferably triethylamine.
  • the reaction is conveniently carried out using an organic solvent, such as dimethylformamide (DMF), preferably in an inert atmosphere. Suitable reaction temperatures are from 0° C to 40° C, preferably room temperature.
  • DMF dimethylformamide
  • Process variant (I) may be carried out using known procedures for reacting amines with acyl-imidazoles, isocyanates or arylcarbamates, or analogously as hereinafter described in the Examples.
  • T in formula X is preferably imidazolyl.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran or N-methyl-pyrrolidone (NMP), preferably in the presence of a base, for example triethylamine.
  • NMP N-methyl-pyrrolidone
  • suitable reaction temperatures are from 0° C to 40° C, preferably room temperature.
  • suitable reaction temperatures are from room temperature to 120° C, preferably 80° C to 110° C, especially about 110° C.
  • Process variant (J) may be carried out using known procedures for reacting N-heterocycles with acyl-imidazoles, isocyanates or arylcarbamates, or analogously as hereinafter described in the Examples.
  • T in formula XIIe is preferably imidazolyl.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran or N-methyl-pyrrolidone (NMP).
  • NMP N-methyl-pyrrolidone
  • suitable reaction temperatures are from 0° C to 40° C, preferably room temperature.
  • suitable reaction temperatures are from room temperature to 120° C, preferably 80° C to 110° C, especially about 110° C.
  • Process variant (K) may be carried out using known procedures for reacting amines with acyl-imidazoles, isocyanates or arylcarbamates, or analogously as hereinafter described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran.
  • suitable reaction temperatures are from 0° C to 40° C, preferably room temperature.
  • suitable reaction temperatures are from room temperature to 120° C, preferably 80° C to 110° C, especially about 110° C.
  • the protecting groups may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, Third Edition, 1999 , which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
  • Compounds of formula II may be prepared by deprotecting a compound of formula XIII where R 2 and R 3 are as hereinbefore defined, and each L is C 1 -C 8 -alkyl, using known procedures for cleaving ester bonds, or analogously as herein described in the Examples.
  • the reaction is carried out using a strong organic acid, such as trifluoroacetic acid.
  • Each L is preferably t-butyl.
  • the reaction is conveniently carried out using an organic solvent, for example dichloromethane. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula IV may be prepared by reacting a compound of formula II where R 3 is halo, with a compound of formula III or IIIa wherein R 1 is as hereinbefore defined, X is a leaving group, preferably halo, and K is hydrogen or C 1 -C 8 -alkyl, in the presence of a base, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran.
  • the base is preferably diisopropylethylamine. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula VI may be prepared by reacting a compound of formula KIV where R 3 is as hereinbefore defined and X is halo, with a compound of formula III or IIIa, wherein R 1 is as hereinbefore defined, X is a leaving group, preferably halo, and K is hydrogen or C 1 -C 8 -alkyl, in the presence of a base, wherein R 1 is as hereinbefore defined and X is halo, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran, preferably in the presence of a base, for example diisopropylethylamine. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula VIII may be prepared by reacting a compound of formula XV where R 1 , R 2 and R 3 are as hereinbefore defined and L is C 1 -C 8 -alkyl, with a dihydroxylating agent, such as osmium tetroxide (OsO 4 ), either in a stoichiometrical amount or a catalytic amount, preferably together with a re-oxidant, such as N-methylmorpholine N-oxide (NMO), or alternatively using AD-mix- ⁇ or AD-mix- ⁇ , or analogously as herein described in the Examples.
  • L is preferably t-butyl.
  • the reaction is conveniently carried out using an organic solvent, for example THF. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula IX may be prepared by reacting a compound of formula XVI where R 1 and R 2 are as hereinbefore defined and L is C 1 -C 8 -alkyl, is reacted with a compound of formula XVII wherein Y is C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, or analogously as herein described in the Examples.
  • Suitable reaction temperatures from 80° C to 130° C, preferably 90° C to 120° C room temperature, especially about 105° C.
  • Compounds of formula XIII may be prepared by reacting a compound of formula XVIII where R 2 and R 3 are as hereinbefore defined, and each L is C 1 -C 8 -alkyl or benzyl, with a hydroxylating agent, such as osmium tetroxide (OsO 4 ), either in a stoichiometrical amount or a catalytic amount, preferably together with a re-oxidant, such as N-methylmorpholine N-oxide (NMO), or alternatively using AD-mix- ⁇ or AD-mix- ⁇ , or analogously as herein described in the Examples.
  • L 1 and L 2 are preferably t-butyl.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XIV may be prepared by reacting a compound of formula XIX where R 3 and X are as hereinbefore defined, and each L is C 1 -C 8 -alkyl or benzyl, with a strong organic acid, such as trifluoroacetic acid, or analogously as herein described in the Examples. Each L is preferably t-butyl.
  • the reaction is conveniently carried out using an organic solvent, for example dichloromethane. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XV may be prepared by reacting a compound of formula XX where R 3 is as hereinbefore defined, X is halo and L is C 1 -C 8 -alkyl or benzyl, with a compound of formula VII, wherein R 2 is as hereinbefore defined, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran, preferably in an inert atmosphere, for example in argon.
  • Suitable reaction temperatures from 30° C to 70° C, preferably from 40° C to 60° C, especially about 50° C.
  • Compounds of XVI may be prepared by reacting a compound of formula XXI where R 2 is as hereinbefore defined and L' is C 1 -C 8 -alkyl or benzyl but preferably methyl, with a compound of formula III or IIIa, wherein R 1 is as hereinbefore defined, X is a leaving group, preferably halo, and K is hydrogen or C 1 -C 8 -alkyl, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran, preferably in the presence of a base, for example diisopropylethylamine. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XVIII may be prepared by reacting a compound of formula XXII where R 2 and R 3 are as hereinbefore defined, and L" is C 1 -C 8 -alkyl preferably methyl or ethyl, with a compound of formula XXIII where each L is C 1 -C 8 -alkyl or benzyl, preferably benzyl, and preferably in the presence of a catalyst, such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • a catalyst such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • each L is t-butyl or benzyl.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example
  • Compounds of formula XIX may be prepared by reacting a compound of formula XXIV where R 3 and X are as hereinbefore defined, and each L is C 1 -C 8 -alkyl or benzyl, with a hydroxylating agent, such as osmium tetroxide (OsO 4 ), either in a stoichiometrical amount or a catalytic amount, preferably together with a re-oxidant, such as N-methylmorpholine N-oxide (NMO), or alternatively using AD-mix- ⁇ or AD-mix- ⁇ , or analogously as herein described in the Examples.
  • Each L is preferably t-butyl.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XX may be prepared by reacting a compound of formula XXV where R 3 is as hereinbefore defined, and L" is C 1 -C 8 -alkyl, with a compound of formula XXVa where R 1 is as hereinbefore defined, and L is C 1 -C 8 -alkyl or benzyl, preferably in the presence of a catalyst, such as that generated from tetrakis(triphenyl-phosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • a catalyst such as that generated from tetrakis(triphenyl-phosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • L is t-butyl or benzyl.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran
  • each L is C 1 -C 8 -alkyl or benzyl and L' is C 1 -C 4 -alkyl, is reacted with a strong acid, for example hydrochloric acid using known procedures for cleaving esters bonds, or analogously as herein described in the Examples.
  • a strong acid for example hydrochloric acid
  • each L is t-butyl or benzyl and L a is methyl or ethyl.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example dioxane. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XXII may be prepared by reacting a compound of formula XXVII where R 2 and R 3 are as hereinbefore defined, with an acylating agent such as a carboxylic acid C 1 -C 8 -alkyl ester, for example 3-oxy-benzotriazole-1-carboxlic acid ethyl ester, in the presence of a base, such as diisoproplylamine, and a catalyst, such as 4-dimethylaminopyridine (DMAP), or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated THF. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XXIV may be prepared by reacting a compound of formula XXVIII where R 3 and X are as hereinbefore defined, and L" is C 1 -C 8 -alkyl, with a compound of formula XXIII where each L is C 1 -C 8 -alkyl or benzyl, preferably in the presence of a catalyst, such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • a catalyst such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • each L is t-butyl or benzyl.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran. Suitable reaction temperatures from
  • Compounds of formula XXV may be prepared by reacting a compound of formula XXIX where R 3 and X are as hereinbefore defined, with an acylating agent such as a carboxylic acid C 1 -C 8 -alkyl ester, for example 3-oxy-benzotriazole-1-carboxlic acid ethyl ester, in the presence of a base, such as diisoproplylamine, and a catalyst, such as 4-dimethylaminopyridine (DMAP), or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran.
  • Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XXVa are commercially available or may be obtained by known procedures for preparing such compounds, for example as described by Ken-ichi Takana et al in Chem. Pharm. Bull. 1988, 36, 3125 , or analogously as herein described in the Examples.
  • Compounds of XXVI may be prepared by reacting a compound of formula XXX where R 2 is as hereinbefore defined, each L is C 1 -C 8 -alkyl and L' is C 1 -C 4 -alkyl or benzyl, preferably benzyl, is reacted with a hydroxylating agent, such as osmium tetroxide (OsO 4 ), either in a stoichiometrical amount or a catalytic amount, preferably together with a re-oxidant, such as N-methylmorpholine N-oxide (NMO), or alternatively using AD-mix- ⁇ or AD-mix- ⁇ , or analogously as herein described in the Examples.
  • a hydroxylating agent such as osmium tetroxide (OsO 4 )
  • OsO 4 osmium tetroxide
  • NMO N-methylmorpholine N-oxide
  • each L is t-butyl and L a is methyl or ethyl.
  • the reaction is conveniently carried out using an organic solvent, for example tetrahydrofuran. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XXVII may be prepared by reacting a compound of formula XXXI where R 2 and R 3 are as hereinbefore defined, with (1S,4R)-cis 4-acetoxy-2-cyclopenten-1-ol in the presence of a base, such as sodium hydride, and a catalyst, such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran or dimethylsulfoxide (DMSO). Suitable reaction temperatures from 40° C to 60° C, preferably about 50° C.
  • Compounds of formula XXVIII may be prepared by reacting a compound of formula XXIX where R 3 and X are as hereinbefore defined, with an acylating agent such as a carboxylic acid C 1 -C 8 -alkyl ester, for example 3-oxy-benzotriazole-1-carboxlic acid ethyl ester, in the presence of a base, such as diisoproplylamine, and a catalyst, such as 4-dimethylaminopyridine (DMAP), or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example THF. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XXIX may be prepared by reacting a compound of formula XXXII where R 3 and X are as hereinbefore defined, with (1S,4R)-cis 4-Acetoxy-2-cyclopenten-1-ol in the presence of a base, such sodium hydride, and a catalyst, such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran or dimethylsulfoxide (DMSO). Suitable reaction temperatures from 40° C to 60° C, preferably about 50° C.
  • Compounds of formula XXX may be prepared by reacting a compound of formula XXXIII where R 2 is as hereinbefore defined, L" is C 1 -C 8 -alkyl or benzyl, and L' is C 1 -C 4 -alkyl, with a compound of formula XXIII where each L is C 1 -C 8 -alkyl, preferably in the presence of a catalyst, such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • a catalyst such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • each L" is t-butyl or benzyl and L' is methyl or ethyl.
  • the reaction is conveniently carried out in an inert environment, for example in argon,
  • Compounds of formula XXXI may be prepared by reacting a compound of formula XXXII where R 3 is as hereinbefore defined and X is halo, with a compound of formula VII where R 2 is as hereinbefore defined, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example tetrahydrofuran. Suitable reaction temperatures from 40° C to 60° C, preferably about 50° C.
  • Compounds of formula XXXIII may be prepared by reacting a compound of formula XXXIV where R 2 and L' are as hereinbefore defined, with a compound of formula XXXV where L" is C 1 -C 8 -alkyl, preferably methyl or ethyl, and X is halo, preferably chloro, or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran, preferably in the presence of a base, for example pyridine. Suitable reaction temperatures from 0° C to 40° C, preferably room temperature.
  • Compounds of formula XXXIV may be prepared by reacting a compound of formula XXXVI where R 2 is as hereinbefore defined and L' is C 1 -C 4 -alkyl, preferably methyl or ethyl, with (1S,4R)-cis 4-acetoxy-2-cyclopenten-1-ol in the presence of a base, such sodium hydride, and a catalyst, such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • a base such sodium hydride
  • a catalyst such as that generated from tetrakis(triphenylphosphine)palladium and triphenylphosphine, or analogously as herein described in the Examples.
  • reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example deoxygenated tetrahydrofuran or dimethyl sulfoxide.
  • organic solvent for example deoxygenated tetrahydrofuran or dimethyl sulfoxide.
  • Compounds of formula XXXVI may be prepared by reacting a salt compound of formula XXXVI where R 3 is as hereinbefore defined and L is C 1 -C 8 -alkyl, with a silating agent, for example (N,O-bis(trimethylsilyl)acetamide), or analogously as herein described in the Examples.
  • a silating agent for example (N,O-bis(trimethylsilyl)acetamide), or analogously as herein described in the Examples.
  • the reaction is conveniently carried out in an inert environment, for example in argon, using an organic solvent, for example dry chloroform. Suitable reaction temperatures from 60° C to 100° C, preferably about 80° C.
  • the silylated intermediate thus formed is treated with methanol to give the free base.
  • Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation.
  • Compounds of formula I can be recovered from reaction mixtures and purified in a conventional manner.
  • Isomers, such as stereoisomers may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • Compounds of formula I and their pharmaceutically acceptable salts are useful as pharmaceuticals.
  • they activate the adenosine A 2A receptor, i.e. they act as A 2A receptor agonists.
  • Their properties as A 2A agonists may be demonstrated using the method described by L. J. Murphree et al in Molecular Pharmacology 61, 455-462 (2002 ).
  • K i values below 1.0 ⁇ M in the above assay For example, the compounds of Examples 1, 2, 4, 6, 12, 14, 20, 33, 38, 39, 42, 47, 55 and 61 have K i values of 0.582, 0.018, 0.057, 0.008, 0.003, 0.690, 0.008, 0.052, 0.002, 0.003, 0.002, 0.002, 0.004 and 0.009 ⁇ M respectively.
  • agents of the invention are useful in the treatment of conditions which respond to the activation of the adenosine A 2A receptor, particularly inflammatory or allergic conditions. Treatment in accordance with the invention may be symptomatic or prophylactic.
  • agents of the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodelling or disease progression.
  • Inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • asthma inflammatory or obstructive airways diseases to which the present inventi on is applicable
  • asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome”.)
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. cortico-steroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and cha-racterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • agents of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hyper-eosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitili go, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • Agents of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune haematological disorders (e.g.
  • haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunct-ivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • Other diseases or conditions which may be treated with agents of the invention include diabetes, e.g.
  • diabetes mellitus type I (juvenile diabetes) and diabetes mellitus type II, diarrheal diseases, ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, conditions characterised by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma, ischemic tissue/organ damage from reperfusion and bedsores.
  • retinopathy such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy
  • an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. a mouse or rat model, of airways inflammation or other inflammatory conditions, for example as described by Szarka et al, J. Immunol. Methods (1997) 202:49-57 ; Renzi et al, Am. Rev. Respir. Dis. (1993) 148:932-939 ; Tsuyuki et al., J. Clin. Invest. (1995) 96:2924-2931 ; Cernadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8 ; and Fozard et al (2002) European Journal of Pharmacological 438, 183-188 .
  • the agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • An agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167 , WO 02/12266 , WO 02/100879 , WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668 , WO 03/48181 , WO 03/62259 , WO 03/64445 , WO 03/72592 , WO 04/39827 and WO 04/66920 ; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874 , WO 00/00531 , WO 02/10143 , WO 03/82280 , WO 03/82787 , WO 03/862
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021 , US 3714357 , US 5171744 , US 2005/171147 , US 2005/182091 , WO 01/04118 , WO 02/00652 , WO 02/51841 , WO 02/53564 , WO 03/00840 , WO 03/33495 , WO 03/53966 , WO 03/87094 , WO 04/018422 , WO 04/05285 and WO 05/077361 .
  • anticholinergic or antimuscarinic agents in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described
  • Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist / muscarinic antagonists such as those disclosed in US 2004/0167167 , US 2004/0242622 , US 2005/182092 , WO 04/74246 and WO 04/74812 .
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, ioratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in JP 2004107299 , WO 03/099807 and WO 04/026841 .
  • agents of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/665
  • the invention also provides a method for the treatment of a condition responsive to activation of the adenosine A 2A receptor, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula I in free form or in the form of a pharmaceutically acceptable salt.
  • a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to activation of the adenosine A 2A receptor, particularly an inflammatory or obstructive airways disease.
  • the agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • any appropriate route e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • the composition may contain a co-therapeutic agent such as an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol (up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan trioleate, and/or one or more bulking agents such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, for example, the compound of formula I having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, for example, the compound of formula I either dissolved, or suspended, in a vehicle containing water, a co-solvent such as ethanol or propylene glycol and a stabiliser, which may be a surfactant.
  • the invention includes (A) a compound of formula I in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g- micronised, form, (B) an inhalable medicament comprising a compound of formula I in inhalable form; (C) a pharmaceutical product comprising a compound of formula I in inhalable form in association with an inhalation device; and (D) an inhalation device containing a compound of formula I in inhalable form.
  • A a compound of formula I in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g- micronised, form
  • B an inhalable medicament comprising a compound of formula I in inhalable form
  • C a pharmaceutical product comprising a compound of formula I in inhalable form in association with an inhalation device
  • an inhalation device containing a compound of formula I in inhalable form.
  • Dosages of compounds of formula I employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration.
  • suitable daily dosages for administration by inhalation are of the order of 0.005 to 10 mg
  • suitable daily doses are of the order of 0.05 to 100 mg.
  • Preferred compounds of formula I include those shown in Table 1 below. Methods for preparing such compounds are described hereinafter. The table also shows mass spectrometry, MH + (ESMS), data. The Examples are in free form, except for Examples 1-3, 7, 9-11 and 17-37, which are trifluoroacetate salts. TABLE 1 Ex.
  • CDI 1,1'-carbonyldiimidazole
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • LCMS liquid chromatographic mass spectroscopy
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thinlayer chromatography.
  • This compound is prepared from 2-isopropyl-5-oxo-5,6,7,8-tetrahydro-imidazo[1,5-c]pyrimidin-2-ium iodide by the procedure of Rahul Jain and Louis A. Cohen Tetrahedron 1996, 52, 5363 . 1 H nmr (MeOD, 400 MHz); 7.60(s, 1H), 6.95(s, 1H), 4.40(m, 1H), 2.90(t, 2H), 2.70(t, 2H), 1.45(d, 6H).
  • the title compound is prepared from propyl-carbamic acid tert-butyl ester using the procedure described by Ken-ichi Takana et al in Chem. Pharm. Bull. 1988, 36, 3125 . 1 H nmr (CDCl 3 , 400 MHz); 7.25(br s, 1H), 2.75(q, 2H), 1.50(s, 9H), 1.15(t, 3H).
  • 4,4'-Dimethoxybenzophenone (25 g, 103 mmol) is suspended in ethanol (150 ml) and pyridine (30 ml). Hydroxylamine hydrochloride (21.50 g, 310 mmol) is added and the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer dried is over MgSO 4 , filtered and the solvent removed in vacuo. The title compound is obtained following crystallisation from ethylacetate/ cyclohexane.
  • Bis-(4-methoxy-phenyl)-methanone oxime (20 g, 77.82 mmol) is suspended in ammonia .880 (450 ml) and ethanol (90 ml). Ammonium acetate (3.00 g, 38.91 mmol) is added followed by the portionwise addition of zinc dust (25.29 g, 389.10 mmol). Once the addition is complete the reaction mixture is slowly heated to 50°C. When the effervescence has ceased the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 4 hours. The reaction mixture is allowed to cool and ethyl acetate is added (250 ml). The reaction mixture is filtered through CeliteTM and the phases are separated.
  • the compound is used in solution in subsequent reactions.
  • This solution consists of the imidazole-urea intermediate (C) together with variable amounts of the corresponding isocyanate and imidazole which result from reversible thermal elimination of imidazole under the reaction conditions.
  • This solution is used in the subsequent steps since the imidazole-urea intermediate and isocyanate intermediate are equally suitable as precursors to ureas.
  • the titled compound is prepared analogously to Intermediate D by replacing (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester and replacing 2-bromopyridine with 2-chloropyridine.
  • the titled compound is prepared analogously to 9-[(1R,2S,3R,4S)-4-(tert-butoxycarbonylpropionyl-amino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Example 38) by replacing 9-[(1R,4S)-4-(tert-butoxycarbonylpropionyl-amino)-cyclopent-2-enyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester with [(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-propionyl-carbamic acid tert-butyl ester.
  • 2,6-Dichloropurine (9.50 g, 50.29 mmol) is dissolved in THF (200 ml) under an atmosphere of argon.
  • Diisopropylamine (7.14 g, 55.32 mmol) is added followed by C,C-bis-(4-methoxyphenyl)-methylamine (see preparation of intermediates) (12.22 g, 50.29 mmol) and the reaction mixture is stirred at 50°C.
  • the reaction is shown to be complete by LCMS after 5 days.
  • the solvent is removed in vacuo and replaced with MeOH (250 mL).
  • the resulting precipitate is filtered off and dried to give the title compound.
  • N-[(1S,2R,3S,4R)-4-(6-Amino-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (10.6mg, 31 ⁇ mol), 1-hexyne (25.4mg, 310 ⁇ mol), copper (I) iodide (1.5mg, 7.75 ⁇ mol), dichlorobis(triphenylphosphine)palladium(II) (5.5mg, 7.75 ⁇ mol), triphenylphosphine (4.0mg, 15.5 ⁇ mol), diethylamine (0.4mL) and DMF (0.2mL) are placed in a 0.5-2.5mL microwave vial.
  • the reaction mixture is microwaved in a Personal Chemistry EmrysTM Optimizer microwave reactor at 120°C.
  • the reaction is shown to be complete by LCMS after 1 hour.
  • the solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1% TFA.).
  • MS (ES+) m / e 387 (MH+).
  • the title compound is prepared from di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine using a procedure analogous to that use to prepare (1R,2S,3R,SS)-3-(6- ⁇ [bis-(4-methoxy-phenyl)-methyl]-amino ⁇ -2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol.
  • the title compound is prepared from (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol using a procedure analogous to that used to prepare (1S,2R,3S,5R)-3-amino-5-(6-amino-2-chloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate in Example 1.
  • the title compound is prepared from (1S,2R,3S,SR)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate and propionyl chloride using a procedure analogous to that used to prepare N-[(1S,2R,3S,4R)-4-(6-amino-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide trifluoroacetate in Example 2.
  • MS (ES+) m / e 360 (MH+).
  • N-[(1S,2R,3S,4R)-4-(2,6-Dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide 160 mg, 0.44 mmol
  • THF 5 ml
  • Diisopropylamine 69 mg, 0.53 mmol
  • 2,2-diphenylethylamine 96 mg, 0.49 mmol
  • the reaction is shown to be complete by LCMS after 2 hours.
  • the final compound of Example 4 may also be prepared using the following process:
  • the title compound is prepared from ⁇ 2-chloro-9-[(1R,4S)-4-(di-Boc-amino)-cyclopent-2-enyl]-9H-purin-6-yl ⁇ -(2,2-diphenyl-ethyl)-amine using a procedure analogous to that of Prep. 11.
  • 1 H nmr (MeOD, 400 MHz); 8.05(s, 1H), 7.35-7.15(m, 10H), 4.70-4.55(m, 4H), 4.50(m, 1H), 4.35(m, 1H), 4.20(m, 2H), 2.55(m, 1H), 2.45(m, 1H), 1.60(s, 18H).
  • the free-base is formed as follows: N- ⁇ (1S,2R,3S,4R)-4-[2-(4-Amino-cyclohexylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide trifluoroacetate (300 mg, 0.50 mmol) is loaded onto DOWEX® 50WX2-200 ion exchange resin (pre-washed with water). The resin is eluted with water until neutral pH and then with methanol: ammonia .880 (1: 1) to elute the free base.).
  • the title compound is prepared from N-[(1S,2R,3S,4R)-4-(2,6-Dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide using a procedure analogous to that used to prepare the compound of Example 3.
  • This compound is prepared from N-[(1S,2R,3S,4R)-4-(2,6-Dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide using histamine in a procedure analogous to that used to prepare the compound of Example 5.
  • the title compound is prepared using N -(aminoethyl)piperidine in a procedure analogous to that used to prepare the compound of Example 5.
  • This compound is prepared from N- ⁇ (1S,2R,35,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide (compound of Example 4) and 2-(1-ethyl-1H-imidazol-4-yl)-ethylarnine using a procedure analogous to that of Example 21.
  • This compound is prepared from N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide (compound of Example 4) and 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine using a procedure analogous to that of Example 9 for the desired salt.
  • Cyclopropanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -amide and N- ⁇ (1S,2R,3S,4R)-4-[2-Chloro-6-(2,2-diphenylethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -butyramide are prepared using a procedure analogous to that of Example 4 in which propionyl chloride is replaces with the appropriate acylating agent.
  • the title compound is prepared from carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (an intermediate for preparing the compound of Example 4) and propionyl-carbamic acid tert-butyl ester (see preparation of intermediates) using a procedure analogous to that of di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine (another intermediate for preparing the compound of Example 4).
  • the title compound is prepared from ⁇ (1S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-cyclopent-2-enyl ⁇ -propionyl-carbamic acid tert-butyl ester using a procedure analogous to that of (1R,2S,3R,5S)-3-(6- ⁇ [bis-(4-methoxy-phenyl)-methyl]-amino ⁇ -2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol (see Example 1).
  • This compound is prepared from ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionyl-carbamic acid tert-butyl ester using a procedure analogous to that of Example 3.
  • Cyclopropanecarboxylic acid ((1S,2R,3S,4R)-4- ⁇ 6-(2,2-diphenyl-ethylamino)-2-[2-(1-isopropyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-amide trifluoroacetate
  • 2,6-Dichloropurine (20.00 g, 106 mmol) is dissolved in THF (250 ml) under an atmosphere of argon.
  • Diisopropylamine (16.38 g, 127 mmol) is added followed by 2,2-diphenylethylamine (25.00 g, 127 mmol) and the reaction mixture is stirred at 50°C.
  • the reaction is shown to be complete by LCMS after 6 hours. 50% of the solvent is removed in vacuo and replaced with MeOH. The resulting precipitate is filtered off and dried to give the title compound.
  • the solvent is removed under reduced pressure and the residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1 % TFA) : water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1 % TFA) : water (0.1% TFA) (100:0 by volume) to afford the title compound.
  • Cyclopropanecarboxylic acid ((1S,2R,3S,4R)-4- ⁇ 6-(2,2-diphenyl-ethylamino)-2-[2-(1-isopropyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-amide trifluoroacetate
  • reaction mixture is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA) : water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA) : water (0.1% TFA) (100:0 by volume) to afford the title compound.
  • LCMS electrorospray
  • Cyclobutanecarboxylic acid ((1S,2R,3S,4R)-4- ⁇ 6-(2,2-diphenyl-ethylamino)-2-[2-(1-isopropyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-amide trifluoroacetate
  • Cyclobutanecarboxylic acid ((1S,2R,3S,4R)-4- ⁇ 6-(2,2-diphenyl-ethylamino)-2-[2-(1-isopropyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-amide trifluoroacetate
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -amide, 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine (see preparation of intermediates) (30 mg, 0.2 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared by the same method as cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -amide from (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) and butyryl chloride to afford the title compound (48 mg).
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -butyramide, 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine (see preparation of intermediates) (30 mg, 0.2 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared by the same method as cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R) -4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -amide from (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) and isobutyryl chloride to afford the title compound.
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -isobutyramide, 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine (see preparation of intermediates) (30 mg, 0.2 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -2-phenyl-acetamide, 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine (see preparation of intermediates) (30 mg, 0.2 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -amide (an intermediate for preparing Example 23), 1-(2-aminoethyl)piperidine (0.057 ml, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -butyramide (an intermediate for preparing Example 24), 1-(2-aminoethyl)-piperidine (0.057 ml, 0.4 mmol) and sodium iodide mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -isobutyramide (an intermediate for preparing Example 25), 1-(2-aminoethyl)-piperidine (0.057 ml, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -2-phenyl-acetamide (an intermediate of Example 26), 1-(2-aminoethyl)-piperidine (0.057 ml, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrorospray
  • the title compound is prepared by the same method as cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -amide from (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) and isoxazole-5-carbonyl chloride to afford the title compound.
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using isoxazole-5-carboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -amide, 1-(2-aminoethyl)-piperidine (51 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol).
  • LCMS electrospray
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using cyclopropanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -amide (an intermediate for preparing Example 22), (R)-pyrrolidin-3-ylamine (34 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol) to give a mixture of two regioisomers which are purified by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1% TFA) to give a product which is predominantly cyclopropanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-((R)-3-aminopyrrolidin-1-yl)-6
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -amide (an intermediate for preparing Example 23), (R)-pyrrolidin-3-ylamine (34 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol) to give a mixture of two regioisomers which are purified by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1 % TFA) to give a product which is predominantly cyclobutanecarboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-((R)-3-aminopyrrolidin-1-yl
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -2-phenyl-acetamide (an intermediate for preparing Example 26), (R)-pyrrolidin-3-ylamine (34 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol) to give a mixture of two regioisomers which are purified by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water- 0.1% TFA) to give a product which is predominantly N- ⁇ (1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenylethylamino
  • the title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl] -2,3-dihydroxy-cyclopentyl ⁇ -3-phenyl-propionamide, (R)-pyrrolidin-3-ylamine (34 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol) to give a mixture of two regioisomers which are purified by reverse phase column chromatography (IsoluteTM C18, 0-100% acetonitrile in water - 0.1 % TFA) to give a product which is predominantly N- ⁇ (1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-
  • N- ⁇ (1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide (30 mg, 0.04 mmol) is dissolved in toluene (2 ml) and i PrOH(1 ml).
  • N -[1-(2-Pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide (prepared using the procedure described in international patent application WO 01/94368 ) (12 mg, 0.044 mmol) is added as a solution in dichloromethane. The reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 24 hours. The solvent is removed in vacuo.
  • Example 37a and 37b are assigned using secondary isotope effects in NMR Spectroscopy. Isotope effects are well established in NMR spectroscopy ( B. A. Bernheim and H. Batiz-Hernandez, Prog. Nucl. Magn. Reson. Spectrosc. 3, 63-85 [1967 ]). Primary isotope effects have been widely studied ( L.J. Altman et al. J. Am. Chem. Soc. 100, 8264-8266 [1978 ]), but it is the secondary isotope shift that has provided important structural information.
  • the magnitude of the two- and three-bond effects vary with the configuration of the carbons, and also the substitution and hydrogen bonding of these exchangeable groups. It is these signal multiplet formations and magnitude of isotope effects are used to unambiguously assign and confirm the structures of Example 37a and Example 37b.
  • Example 37a is bonded to two NH groups
  • Example 37b is bonded to one NH group and to the fully substituted nitrogen of the proline ring.
  • 6-(2,2-Diphenyl-ethylamino)-9-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (2.80 g, 6.14 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry tetrahydrofuran (30 ml) is added followed by dry pyridine (0.97 g, 12.3 mmol). Ethyl chloroformate (2.66 g, 24.6 mmol) is added slowly and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours.
  • 6-(2,2-Diphenyl-ethylamino)-9-((1R,4S)-4-ethoxycarbonyloxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (2.2 g, 4.2 mmol) is dissolved in deoxygenated tetrahydrofuran. The resultant solution is stirred under an atmosphere of argon at room temperature.
  • the title compound is prepared from 9-((1R,4S)-4-di-tert-butoxycarbonylamino-cyclopent-2-enyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(di-Boc-amino)-cyclopentane-1,2-diol.
  • This compound which is the trifluoroacetate salt of the final compound of Example 37, is prepared using a method that is analogous to that used to prepare 9-((1R,4S)-4-Di-tert-butoxycarbonylamino-cyclopent-2-enyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester by replacing di-t-butyl iminodicarboxylate with propionyl-carbamic acid tert-butyl ester.
  • reaction mixture is partitioned between ethyl acetate and water and the organic portion is dried (MgSO 4 ) and concentrated in vacuo.
  • the titled product is precipitated from methanol. Further product is derived from the mother liquor by chromatography on silica eluting with DCM : methanol (25:1).
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide by replacing 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylaminocyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester with 9-[(1R,2S,3R,4S)-4-(tert-butoxy-carbonyl-propionyl-amino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester.
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid ⁇ 2-[3-(3,4,5,6-tetra-hydro-2H-[1,2]bipyridinyl-4-yl)ureido]-ethyl ⁇ -amide by replacing 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide with ⁇ (1S,2R,3S,4R)-4-[2-(2-Aminoethylcarbamoyl)-6-(2,2-diphenyl-eth
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-4-Amino-2,3-dihydroxycyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester by replacing 9-((1R,-2S,3R,4S)-4-Di-tert-butoxycarbonylamino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester with (1S,2R,3S,4R)-4-(6-(2,2-Diphenyl-ethylamino)-2- ⁇ 2-[3-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-ureido]-ethylcarbamoyl ⁇ -purin-9-yl)-2,
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester by replacing 9-((1R,2S,3R,4S)-,4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenylethylami no)-9H-purine-2-carboxylic acid methyl ester hydrochloride with 9-((1R,2S,3R,4S)-4-Amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid ⁇ 2-[3-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)
  • This compound is prepared analogously to Example 22 by replacing cyclopropane carboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -amide with N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide and by replacing 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine with 1,3-di(R)-pyrrolidin-3-yl-urea.
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid ⁇ 2-[3-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)ureido]-ethyl ⁇ -amide by replacing (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride with 9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxy
  • a mixture comprising 9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenylethylamino)-9H-purine-2-carboxylic acid ⁇ 2-[3-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-ureido]-ethyl)-amide dihydrochloride (0.02 g, 25 ⁇ mol), TEA (0.013 g, 125 ⁇ mol) in THF (2 ml) is treated with acetyl chloride (0.003 g, 40 ⁇ mol).
  • This compound is prepared analogously to cyclopropanecarboxylic acid ((1S,2R,3S,4R)-4- ⁇ 6-(2,2-diphenyl-ethylamino)-2-[2-(1-isopropyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-amide trifluoroacetate by replacing cyclopropanes-carboxylic acid ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -amide with N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid ⁇ 2-[3-((R)-1-pyridin-2-yl-pyrrolidin-3-yl)-ureido]-ethyl ⁇ -amide trifluoroacetate by replacing 1-(2-amino-ethyl)-3-((R)-1-pyridin-2-yl-pyrrolidin-3-yl)-urea with 1-(2-amino-ethyl)-3-((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-urea.
  • This compound is prepared analogously to N-((1S,2R,3S,4R)-4- ⁇ 6-(1-Ethyl-propylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate by replacing N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(1-ethylpropylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide with N-((1S,2R,3S,4R)-4- ⁇ 2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate.
  • N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -propionamide (0.02 g, 0.03 mmol)
  • (3R)-3-(BOC-amino)pyrrolidine 0.028 g, 0.15 mmol
  • sodium iodide 0.004 g, 0.03 mmol
  • Acetonitrile (0.25 ml) and NMP (0.25 ml) are added and the reaction mixture is heated using microwave radiation in a Personal Chemistry EmrysTM Optimizer microwave reactor at 160°C for 30 minutes.
  • DCM (3 ml) and water (3 ml) are added to the reaction mixture and following agitation, the organic portion is separated and treated with TFA (0.5 ml). After standing at room temperature overnight purification is carried out using mass directed preparative LC-MS eluting with acetonitrile: water: trifluoroacetic acid to afford the titled compound.
  • This compound is prepared analogously to N- ⁇ (1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide trifluoroacetate by replacing N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide with N-((1S,2R,3S,4R)-4- ⁇ 2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate.
  • This compound is prepared analogously to N-((1S,2R,3S,4R)-4- ⁇ 6-(1-ethyl-propylamino)-2- ⁇ (R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate by replacing N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(1-ethylpropylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide with N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(3,3-dimethyl-butylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide trifluoroacetate.
  • This compound is prepared analogously to N-((1S,2R,3S,4R)-4- ⁇ 2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl ⁇ -2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 50) by replacing 1-napthalenemethylamine with C-(9H-fluoren-9-yl)-methylamine.
  • This compound is prepared analogously to N- ⁇ (1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide (Example 16) by replacing N- ⁇ (1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenylethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl ⁇ -propionamide (Example 4) with N-((1S,2R,3S,4R)-4- ⁇ 2-chloro-6-[(9H-fluoren-9-ylmethyl)-amino]-purin-9-yl ⁇ -2,3-dihydroxycyclopentyl)-propionamide.
  • This compound is prepared analogously to N- ⁇ (1S,2R,3S,4R)-4-[2- ⁇ (R)-3-[3-(2,6-dichloropyridin-4-yl)-ureido]-pyrrolidin-1-yl ⁇ -6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxycyclopentyl ⁇ -propionamide trifluoroacetate (Example 73) by replacing 2,6-dichloro-4-isocyanato-pyridine with 2-thienyl isocyanate.
  • This compound is prepared analogously to 9-((1R,2S,3R,4S)-4-acetylamino-2,3-dihydroxycyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid ⁇ 2-[3-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-ureido]-ethyl ⁇ -amide trifluoroacetate (Ex.
  • the compound exists as a mixture of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
  • This compound is prepared analogously to 4-methyl-piperazine-1-carboxylic acid ⁇ (R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl ⁇ -amide trifluoroacetate (Example 77) by replacing 1-methyl piperazine with 2-amino pyridine.

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Claims (12)

  1. Verbindung der Formel I
    Figure imgb0531
     in freier Form oder Salzform, worin
    R1 für C1-C8-Alkylcarbonyl, C3-C8-Cycloalkylcarbonyl, -SO2-C1-C8-Alkyl, C7-C14-Aralkylcarbonyl oder -C(=O)-C(=O)-NH-C1-C8-Alkyl, das gegebenenfalls durch R4 substituiert ist, steht;
    R2 für Wasserstoff oder gegebenenfalls durch C6-C10-Aryl substituiertes C1-C8-Alkyl steht;
    R3 für Halogen oder C2-C8-Alkinyl steht, oder R3 für gegebenenfalls durch C3-C8-Cycloalkyl, das gegebenenfalls durch Amino substituiert ist, substituiertes Amino steht,
    oder R3 für gegebenenfalls durch Hydroxy, C6-C10-Aryl oder R5 substituiertes C1-C8-Alkylamino steht, oder R3 für R6, das gegebenenfalls durch Amino oder -NH-C(=O)-NH-R7 substituiert ist, steht,
    oder R3 für -NH-R6, das gegebenenfalls durch -NH-C(=O)-NH-R7 substituiert ist, steht,
    oder R3 für C1-C8-Alkylaminocarbonyl, das gegebenenfalls durch -NH-C(=O)-NH-R8 substituiert ist, steht;
    R4, R5 und R6 jeweils unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls durch C1-C8-Alkyl substituiert ist; und
    R7 und R8 unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls durch Halogen, C1-C8-Alkyl, C1-C8-Alkylsulfonyl oder einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, substituiert ist.
  2. Verbindung nach Anspruch 1, worin
    R1 für C1-C4-Alkylcarbonyl, C3-C5-Cycloalkylcarbonyl, -SO2-C1-C4-Alkyl, C7-C10-Aralkylcarbonyl oder -C (=O) -C (=O) -NH-C1-C4-Alkyl, das gegebenenfalls in einer Position durch R4 substituiert ist, steht;
    R2 für Wasserstoff, unsubstituiertes C1-C6-Alkyl oder gegebenenfalls in einer Position durch C6-C10-Aryl substituiertwa C1-C5-Alkyl steht;
    R3 für Halogen oder C2-C6-Alkinyl steht,
    oder R3 für gegebenenfalls in einer Position durch C3-C8-Cycloalkyl, das gegebenenfalls in einer Position durch Amino substituiert ist, substituiertes Amino steht,
    oder R3 für gegebenenfalls in einer oder zwei Positionen durch Hydroxy, Phenyl oder R5 substituiertes C1-C4-Alkylamino steht,
    oder R3 für R6, das gegebenenfalls in einer Position durch Amino oder -NH-C(=O)-NH-R7 substituiert ist, steht,
    oder R3 für -NH-R6, das gegebenenfalls in einer Position durch -NH-C(=O)-NH-R7 substituiert ist, steht,
    oder R3 für C1-C4-Alkylaminocarbonyl, das gegebenenfalls in einer Position durch -NH-C(=0)-NH-R8 substituiert ist, steht;
    R4, R5 und R6 jeweils unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls in einer Position durch C1-C4-Alkyl substituiert ist; und R7 und R8 unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls in einer oder zwei Positionen durch Halogen, C1-C4-Alkyl, C1-C4-Alkylsulfonyl oder einen 5- oder 6-gliedrigen N-heterocyclischen Ring substituiert ist.
  3. Verbindung nach Anspruch 1, worin
    R1 für C1-C8-Alkylcarbonyl, C3-C8-Cycloalkylcarbonyl, -SO2-C1-C8-Alkyl, C7-C14-Aralkylcarbonyl oder -C(=O)-C(=O)-NH-C1-C8-Alkyl, das gegebenenfalls durch R4 substituiert ist, steht;
    R2 für Wasserstoff oder gegebenenfalls durch C6-C10-Aryl substituiertes C1-C8-Alkyl steht;
    R3 für Halogen oder C2-C8-Alkinyl steht,
    oder R3 für gegebenenfalls durch C3-C8-Cycloalkyl, das gegebenenfalls durch Amino substituiert ist, substituiertes Amino steht,
    oder R3 für gegebenenfalls durch Hydroxy, C6-C10-Aryl oder R5 substituiertes C1-C8-Alkylamino steht, oder R3 für R6, das gegebenenfalls durch Amino oder -NH-C(=O)-NH-R7 substituiert ist, steht,
    oder R3 für C1-C8-Alkylaminocarbonyl, das gegebenenfalls durch -NH-C(=O)-NH-R8 substituiert ist, steht;
    R4, R5 und R6 jeweils unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen; und
    R7 und R8 unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls durch einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, substituiert ist.
  4. Verbindung nach Anspruch 3, worin
    R1 für C1-C4-Alkylcarbonyl, C3-C6-Cycloalkylcarbonyl, -SO2-C1-C4-Alkyl, C7-C10-Aralkylcarbonyl oder -C (=O) -C (=O) -NH-C1-C8-Alkyl, das gegebenenfalls durch R4 substituiert ist, steht;
    R2 für Wasserstoff oder gegebenenfalls durch C6-C10-Aryl substituiertes C1-C6-Alkyl steht;
    R3 für Halogen oder C2-C5-Alkinyl steht,
    oder R3 für gegebenenfalls durch C3-C8-Cycloalkyl, das gegebenenfalls durch Amino substituiert ist, substituiertes Amino steht,
    oder R3 für gegebenenfalls durch Hydroxy, C6-C10-Aryl oder R5 substituiertes C1-C4-Alkylamino steht, oder R3 für R6, das gegebenenfalls durch Amino oder -NH-C(=O)-NH-R7 substituiert ist, steht,
    oder R3 für C1-C4-Alkylaminocarbonyl, das gegebenenfalls durch -NH-C(=O)-NH-R8 substituiert ist, steht;
    R4, R5 und R6 jeweils unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen; und
    R7 und R8 unabhängig voneinander für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, stehen, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls durch einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, substituiert ist.
  5. Verbindung der Formel I nach Anspruch 1, worin R1, R2 und R3 die in den folgenden Tabellen angegebenen Bedeutungen besitzen: R1 R2 R3
    Figure imgb0532
         -H -Cl
    Figure imgb0533
         -H
    Figure imgb0534
    Figure imgb0535
         -H
    Figure imgb0536
    Figure imgb0537
    Figure imgb0538
         -Cl
    Figure imgb0539
    Figure imgb0540
    Figure imgb0541
    Figure imgb0542
    Figure imgb0543
    Figure imgb0544
    Figure imgb0545
    Figure imgb0546
    Figure imgb0547
    Figure imgb0548
    Figure imgb0549
    Figure imgb0550
    Figure imgb0551
    Figure imgb0552
    Figure imgb0553
    Figure imgb0554
    Figure imgb0555
    Figure imgb0556
    Figure imgb0557
    Figure imgb0558
    Figure imgb0559
    Figure imgb0560
    Figure imgb0561
         -Cl
    Figure imgb0562
    Figure imgb0563
         -Cl
    Figure imgb0564
    Figure imgb0565
         -Cl
    Figure imgb0566
    Figure imgb0567
    Figure imgb0568
    Figure imgb0569
    Figure imgb0570
    Figure imgb0571
    Figure imgb0572
    Figure imgb0573
    Figure imgb0574
    Figure imgb0575
    Figure imgb0576
    Figure imgb0577
    Figure imgb0578
    Figure imgb0579
    Figure imgb0580
    Figure imgb0581
    Figure imgb0582
    Figure imgb0583
    Figure imgb0584
         -H
    Figure imgb0585
    Figure imgb0586
    Figure imgb0587
    Figure imgb0588
    Figure imgb0589
    Figure imgb0590
    Figure imgb0591
    Figure imgb0592
    Figure imgb0593
    Figure imgb0594
    Figure imgb0595
    Figure imgb0596
    Figure imgb0597
    Figure imgb0598
    Figure imgb0599
    Figure imgb0600
    Figure imgb0601
    Figure imgb0602
    Figure imgb0603
    Figure imgb0604
    Figure imgb0605
    Figure imgb0606
    Figure imgb0607
    Figure imgb0608
    Figure imgb0609
    Figure imgb0610
    Figure imgb0611
    Figure imgb0612
    Figure imgb0613
    Figure imgb0614
    Figure imgb0615
    Figure imgb0616
    Figure imgb0617
    Figure imgb0618
    Figure imgb0619
    Figure imgb0620
    Figure imgb0621
    Figure imgb0622
    Figure imgb0623
    Figure imgb0624
    Figure imgb0625
    Figure imgb0626
    Figure imgb0627
    Figure imgb0628
    Figure imgb0629
    Figure imgb0630
    Figure imgb0631
    Figure imgb0632
    Figure imgb0633
    Figure imgb0634
    Figure imgb0635
    Figure imgb0636
    Figure imgb0637
    Figure imgb0638
    Figure imgb0639
    Figure imgb0640
    Figure imgb0641
    Figure imgb0642
    R1 R2 R3
    Figure imgb0643
    Figure imgb0644
    Figure imgb0645
    Figure imgb0646
    Figure imgb0647
    Figure imgb0648
    Figure imgb0649
    Figure imgb0650
    Figure imgb0651
    Figure imgb0652
    Figure imgb0653
    Figure imgb0654
    Figure imgb0655
    Figure imgb0656
    Figure imgb0657
    Figure imgb0658
    Figure imgb0659
    Figure imgb0660
    Figure imgb0661
    Figure imgb0662
    Figure imgb0663
    Figure imgb0664
    Figure imgb0665
    Figure imgb0666
    Figure imgb0667
    Figure imgb0668
    Figure imgb0669
    Figure imgb0670
    Figure imgb0671
    Figure imgb0672
    Figure imgb0673
    Figure imgb0674
    Figure imgb0675
    Figure imgb0676
    Figure imgb0677
         -Cl
    Figure imgb0678
    Figure imgb0679
         -Cl
    Figure imgb0680
    Figure imgb0681
         -Cl
    Figure imgb0682
    Figure imgb0683
         -Cl
    Figure imgb0684
    Figure imgb0685
    Figure imgb0686
    Figure imgb0687
    Figure imgb0688
    Figure imgb0689
    Figure imgb0690
    Figure imgb0691
    Figure imgb0692
    Figure imgb0693
    Figure imgb0694
    Figure imgb0695
    Figure imgb0696
    Figure imgb0697
    Figure imgb0698
    Figure imgb0699
    Figure imgb0700
    Figure imgb0701
    Figure imgb0702
    Figure imgb0703
    Figure imgb0704
    Figure imgb0705
    Figure imgb0706
    Figure imgb0707
    Figure imgb0708
    Figure imgb0709
    Figure imgb0710
    R1 R2 R3
    Figure imgb0711
    Figure imgb0712
    Figure imgb0713
    Figure imgb0714
    Figure imgb0715
    Figure imgb0716
    Figure imgb0717
    Figure imgb0718
    Figure imgb0719
    Figure imgb0720
    Figure imgb0721
    Figure imgb0722
    Figure imgb0723
    Figure imgb0724
    Figure imgb0725
    Figure imgb0726
    Figure imgb0727
    Figure imgb0728
    Figure imgb0729
    Figure imgb0730
    Figure imgb0731
    Figure imgb0732
    Figure imgb0733
    Figure imgb0734
    Figure imgb0735
    Figure imgb0736
    Figure imgb0737
    Figure imgb0738
    Figure imgb0739
    Figure imgb0740
    Figure imgb0741
    Figure imgb0742
    Figure imgb0743
    Figure imgb0744
    Figure imgb0745
    Figure imgb0746
    Figure imgb0747
    Figure imgb0748
    Figure imgb0749
    Figure imgb0750
    Figure imgb0751
    Figure imgb0752
    Figure imgb0753
    Figure imgb0754
    Figure imgb0755
    Figure imgb0756
    Figure imgb0757
    Figure imgb0758
    Figure imgb0759
    Figure imgb0760
    Figure imgb0761
    Figure imgb0762
         -H
    Figure imgb0763
  6. Verbindung nach einem der vorhergehenden Ansprüche zur Verwendung als Pharmazeutikum.
  7. Verbindung nach einem der Ansprüche 1 bis 5 in Kombination mit einem entzündungshemmenden oder bronchodilatorischen Arzneistoff oder einem Arzneistoff mit Antihistaminwirkung oder antitussiver Wirkung, wobei die Verbindung und der Arzneistoff in der gleichen pharmazeutischen Zusammensetzung oder in verschiedenen pharmazeutischen Zusammensetzungen vorliegen.
  8. Pharmazeutische Zusammensetzung, umfassend als Wirkstoff eine Verbindung nach einem der Ansprüche 1 bis 5, gegebenenfalls zusammen mit einem pharmazeutisch unbedenklichen Verdünnungsmittel oder Träger.
  9. Pharmazeutische Zusammensetzung nach Anspruch 8, die ferner einen entzündungshemmenden oder bronchodilatorischen Arzneistoff oder einen Arzneistoff mit Antihistaminwirkung oder antitussiver Wirkung umfasst.
  10. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 5 zur Herstellung eines Arzneimittels zur Behandlung eines Leidens, das durch Aktivierung des Adenosin-A2A-Rezeptors vermittelt wird.
  11. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 5 zur Herstellung eines Arzneimittels zur Behandlung einer entzündlichen oder obstruktiven Atemwegserkrankung.
  12. Verfahren zur Herstellung einer Verbindung der Formel I gemäß Anspruch 1 in freier Form oder Salzform, bei dem man
    (i)
    (A) zur Herstellung von Verbindungen der Formel I eine Verbindung der Formel II
    Figure imgb0764
     worin R2 und R3 die in Anspruch 1 angegebene Bedeutung besitzen, in Gegenwart einer Base mit einer Verbindung der Formel III

            R1-xa      III

    oder der Formel IIIa
    Figure imgb0765
     worin R1 für C1-C8-Alkylcarbonyl, C3-C8-Cycloalkylcarbonyl oder C7-C14-Aralkylcarbonyl steht, Xa für eine Abgangsgruppe steht und K für Wasserstoff, C1-C8-Alkyl oder C1-C8-Alkoxy steht, umsetzt;
    (B) zur Herstellung von Verbindungen der Formel I, wobei R3 für durch C3-C8-Cycloalkyl, das gegebenenfalls durch Amino substituiert ist, substituiertes Amino steht oder R3 für gegebenenfalls durch Hydroxy, C6-C10-Aryl oder R5 substituiertes C1-C8-Alkylamino steht oder R3 für R6, das gegebenenfalls durch Amino oder -NH-C(=O)-NH-R7 substituiert ist, steht, eine Verbindung der Formel IV
    Figure imgb0766
     worin R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen und X für Halogen steht, mit einer Verbindung der Formel Va oder Vb
    Figure imgb0767
     worin R3a für C3-C8-Cycloalkyl, das gegebenenfalls durch Amino substituiert ist, oder R3 für gegebenenfalls durch Hydroxy, C6-C10-Aryl oder R5 substituiertes C1-C8-Alkylamino steht, wobei R5 die in Anspruch 1 angegebene Bedeutung besitzt, und R3b und R3c zusammen einen 5- oder 6-gliedrigen heterocyclischen Ring bilden, der ein oder mehrere Stickstoffatome enthält und gegebenenfalls durch Amino oder -NH-C(=O)-NH-R7 substituiert ist, wobei R7 die in Anspruch 1 angegebene Bedeutung besitzt, umsetzt;
    (C) zur Herstellung von Verbindungen der Formel I eine Verbindung der Formel VI
    Figure imgb0768
     worin R1 und R3 die in Anspruch 1 angegebene Bedeutung besitzen und X für Halogen steht, in Gegenwart einer Base mit einer Verbindung der Formel VII

            H2N-R2      VII

    worin R2 die in Anspruch 1 angegebene Bedeutung besitzt, umsetzt;
    (D) zur Herstellung von Verbindungen der Formel I eine Verbindung der Formel VIII
    Figure imgb0769
     worin R1, R2 und R3 die in Anspruch 1 angegebene Bedeutung besitzen und L für C1-C8-Alkyl steht, entschützt;
    (E) zur Herstellung von Verbindungen der Formel I, worin R3 für C1-C9-Alkylamino-carbonyl oder C3-C8-Cycloalkylaminocarbonyl, das durch -NH-C(=O)-NH-R8 substituiert ist, steht, wobei R8 die in Anspruch 1 angegebene Bedeutung besitzt, eine Verbindung der Formel IX
    Figure imgb0770
     worin R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen und Y für C1-C8-Alkyl oder C3-C8-Cycloalkyl steht, in Gegenwart einer Base entweder mit einer Verbindung der Formel X
    Figure imgb0771
     oder mit einer Verbindung der Formel XI

            O=C=N—R8      XI

    worin T für C6-C10-Aryloxy oder einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, steht und R8 die in Anspruch 1 angegebene Bedeutung besitzt, umsetzt;
    (F) zur Herstellung von Verbindungen der Formel I, worin R3 für C2-C8-Alkinyl steht, eine Verbindung der Formel IV, wobei R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen, in Gegenwart einer Base und eines Katalysators mit einer Verbindung der Formel XII

            Rx-C≡C-H     XII

    worin Rx für C1-C8-Alkyl steht, umsetzt;
    (G) zur Herstellung von Verbindungen der Formel I, worin R3 für gegebenenfalls durch -NH-C(=O)-NH-R8 substituiertes C1-C8-Alkylaminocarbonyl steht, eine Verbindung der Formel XIIa
    Figure imgb0772
     worin R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen und Ry für C1-C8-Alkyl steht, gegebenenfalls in Gegenwart einer Base mit einer Verbindung der Formel XIIb
    Figure imgb0773
     worin Rz für C1-C8-Alkyl steht und -NH-C(=O)-NH-R8 die in Anspruch 1 angegebene Bedeutung besitzt, umsetzt; oder
    (H) zur Herstellung von Verbindungen der Formel I, worin R3 für gegebenenfalls durch -NH-C(=O)-NH-R8 substituiertes C1-C8-Alkylaminocarbonyl steht, wobei R8 für einen 5-oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, steht, wobei der Ring durch C1-C8-Alkylsulfonyl substituiert ist, eine Verbindung der Formel I, worin R3 für gegebenenfalls durch -NH-C(=O)-NH-R8 substituiertes C1-C8-Alkylaminocarbonyl steht, wobei R8 für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, steht, in Gegenwart einer Base mit einem Sulfonylierungsmittel umsetzt;
    (I) zur Herstellung von Verbindungen der Formel I, worin R3 für durch -NH-C (=O) -NH-R7 substituiertes R6 steht, wobei R7 die in Anspruch 1 angegebene Bedeutung besitzt, eine Verbindung der Formel XIIc
    Figure imgb0774
     worin R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen und R6 für einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält und in einer Position durch Amino substituiert ist, steht, entweder mit einer Verbindung der Formel Xa
    Figure imgb0775
     oder mit einer Verbindung der Formel XIa

            O=C=N-R7      XIa

    worin T für C6-C10-Aryloxy oder einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, steht und R8 die in Anspruch 1 angegebene Bedeutung besitzt, umsetzt;
    (J) zur Herstellung von Verbindungen der Formel I, worin R3 für durch -NH-C (=O) -NH-R7 substituiertes R6 steht, wobei R7 die in Anspruch 1 angegebene Bedeutung besitzt, eine Verbindung der Formel XIId oder XIIe oder eine geschützte Form davon
    Figure imgb0776
    Figure imgb0777
     wobei R1, R2 und R6 die in Anspruch 1 angegebene Bedeutung besitzen und T für C6-C10-Aryloxy oder einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, steht, mit einer Verbindung der Formel XIIf
    Figure imgb0778
     wobei R3d und R3e zusammen einen 5- oder 6-gliedrigen N-heterocyclischen Ring bilden, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, wobei der 5- oder 6-gliedrige heterocyclische Ring gegebenenfalls durch Halogen, Cyano, Oxo, Hydroxy, Carboxy, Amino, Nitro, C1-C8-Alkoxy, C1-C8-Alkylsulfonyl, Aminocarbonyl, C1-C8-Alkylcarbonyl, C1-C8-Alkyl, das gegebenenfalls durch Aminocarbonyl substituiert ist, oder einen 5- oder 6-gliedrigen N-heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, substituiert ist, umsetzt; oder
    (K) zur Herstellung von Verbindungen der Formel I, wobei R3 für durch -NH-C(=O)-NH-R7 substituiertes R6 steht, wobei R7 die oben angegebene Bedeutung besitzt, eine Verbindung der Formel XIId oder XIIe, wobei R1, R2 und R6 die in Anspruch 1 angegebene Bedeutung besitzen und T für C6-C10-Aryloxy oder einen 5- oder 6-gliedrigen heterocyclischen Ring, der mindestens ein Ringheteroatom aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthält, steht, mit einer Verbindung der Formel XIIg

            H2N-R7      XIIg

    wobei R7 die in Anspruch 1 angegebene Bedeutung besitzt, umsetzt; und
    (ii) jegliche Schutzgruppen abspaltet und die erhaltene Verbindung der Formel Ia in freier Form oder Salzform gewinnt.
EP05797944A 2004-10-22 2005-10-21 Purinderivate zur verwendung als agonisten des adenosin-a-2a-rezeptors Expired - Lifetime EP1805181B1 (de)

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GB0423551A GB0423551D0 (en) 2004-10-22 2004-10-22 Organic compounds
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PCT/EP2005/011344 WO2006045552A1 (en) 2004-10-22 2005-10-21 Purine derivatives for use as adenosin a-2a receptor agonists

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MX2007004735A (es) 2007-06-18
EP2292619A1 (de) 2011-03-09
ES2394453T3 (es) 2013-01-31
US20080200483A1 (en) 2008-08-21
EP1805181A1 (de) 2007-07-11
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US8163754B2 (en) 2012-04-24
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